The Role of Radiotherapy in the Management of Ovarian Cancer Article by: Nagendra Sai Koneru, M.D.

, Anthony Fyles, M.D., William Small Jr., M .D. What is Radiation Therapy? Radiation oncology is a branch of medicine that manipulates ionizing radiation t o treat cancer and other benign diseases. The goal of radiation therapy is to er adicate cancer cells through the delivery of a measured dose of radiation to a p recisely defined tissue volume, while attempting to minimize damage to any healt hy surrounding tissue. In ovarian cancer radiation oncologists work closely with gynecologic oncologists, who are the primary surgical oncologists that treat ov arian cancer, and medical oncologists. Both medical and gynecologic oncologists deliver chemotherapy. Radiation kills cancer cells by damaging the DNA. Tumor cells often have impaire d repair mechanisms that are normally found in healthy cells. Thus, tumor cells can be inherently sensitive to radiation effects. Damage to DNA can occur by dir ect interaction of radiation with a cell s DNA or indirectly by the creation of fr ee radicals that are produced by the interaction of radiation and water within t he cell. Radiation oncologists use linear accelerators to deliver radiation to a patient. Linear accelerators are treatment machines that selectively create high-energy radiation beams which are then directed at a specific target. Epidemiology of Ovarian Cancer There are three primary types of ovarian cancer. Epithelial ovarian cancer compr ises approximately 80%-90% of ovarian cancer and will be the subject of this rev iew. Germ and stromal tumors represent the remaining 10-20%. There are numerous risk factors for ovarian cancer and can include lower number of pregnancies, nulliparity and infertility [3]. Oral contraceptive use has been shown to reduce the risk of ovarian cancer [4]. Women who have a family history of breast cancer or ovarian cancer are at increased risk. Gene mutations in BRC A1 and BRCA2 have been observed in many of these families. Hereditary non-polypo sis colon cancer (HNPCC) is a genetic syndrome that has been associated with col on, endometrial and ovarian cancer. Detection/Screening Routine screening for ovarian cancer has not been recommended because there have been no reliable markers for detecting early epithelial ovarian cancer [1,5] al though routine gynecologic care should still be recommended. The tumor marker CA -125 has been found to be helpful in ovarian cancer screening. The combination o f a pelvic exam, transvaginal ultrasound and a blood test for CA-125 can be offe red for women who are symptomatic or at high risk [1,5]. Clinical Presentation Epithelial ovarian cancer does not present with specific signs or symptoms. Pati ents most commonly present with abdominal distention, however, heartburn, nausea , and lower abdominal pain can also manifest [5]. Ovarian cancer is often metastatic or spread beyond the ovaries at presentation and confined to the ovary in only 23% of cases [6]. The peritoneum is a multilay ered membrane which lines the abdominal cavity, and supports and covers the orga ns within it. The most common route of spread is through the peritoneum (transpe ritoneal) and the disease is confined to the abdominal cavity in 85% of patients [6]. However, ovarian cancer may also spread through the blood or lymphatics. The Federation of International Gynecologists and Obstetrics (FIGO) has grouped

ovarian cancer into four primary stages. Stage I disease is limited to the ovari es. Stage II involves tumor spread in the pelvis beyond the ovaries. Stage III i nvolves spread outside the pelvis but confined within the abdominal cavity or in guinal nodes. Stage IV disease involves tumor in one or both ovaries with distan t metastasis, such as the liver parenchyma or lungs. Microscopically the aggress iveness of the tumor is classified according to its grade, ranging from 1 to 3. Grade 1 shows the least aggressiveness, while grade 3 shows the most. Overall 5 year survival, including all stages for ovarian cancer, is 53% [1]. Fo r early stage disease, the 5 year survival is 94.7%. For intermediate stage dise ase, the 5 year survival is 72% [1]. For late stage, the 5 year survival is 30.7 % [1]. Treatment Surgery is the standard initial management of ovarian cancer [6]. Because of tra nsperitoneal spread and the frequent appearance of upper abdominal disease, pretreatment surgical staging is performed. Surgical staging involves partial oment ectomy, visualization or the entire peritoneum, biopsy of any suspicious or palp able lesions, and cytologic examination of ascites or peritoneal washings from p elvis, paracolic gutters, and diaphragm [6]. Studies have revealed that the amount of residual tumor volume after surgery may impact survival. As residual tumor volume increases, median survival decreases [6]. Cytoreductive surgery is thus recommended for maximum tumor removal [6]. For stage I, grade 1 disease, surgery alone has a 5% relapse rate and is often t he only treatment modality used [6]. Patients with stage I disease with unfavora ble prognostic factors, such as grade 2 or 3, and patients with stage II and III disease are often recommended to have surgery followed by intravenous (IV) carb oplatin and paclitaxel chemotherapy, since there is often at least a 30% risk of recurrence [2]. Recent trials have shown that platinum-based adjuvant chemother apy improved survival and recurrence-free survival in early-stage ovarian cancer [7]. Alternatively, intraperitoneal (IP) chemotherapy, which involves injecting chemotherapy directly into the abdomen, has gained recent attention and may be considered an alternative to IV chemotherapy in certain clinical situations [8]. Adjuvant abdominopelvic radiotherapy can also be used in selected patients [9]. Rationale for Radiation Therapy Evidence that radiation therapy is an effective adjuvant therapy in certain stag es and extents of ovarian cancer has been proven in several trials [6]. For earl y and intermediate stage disease, trials have shown that radiotherapy to the who le abdomen following surgery to be more effective than certain chemotherapy and pelvic radiation. Although there have been no randomized trials comparing platin um based chemotherapy to whole abdominal therapy, platinum based chemotherapy ha s largely supplanted the use of radiotherapy in the United States. However, radi otherapy does have a role in both cure and symptom control in patients with ovar ian cancer. A Princess Margaret Hospital randomized trial of 147 patients compared pelvic ra diotherapy alone or with chlorambucil chemotherapy to whole abdomen radiotherapy , in patients with stages I-III disease. After a 7 year follow-up, the 10-year d ifference in survival was significantly higher in the 76 patients treated with p elvis plus whole abdomen radiotherapy compared to the 71 patients treated with p elvic irradiation and chlorambucil (46% vs 31%, p=0.05) [10]. The survival benef it was only seen in patients with small macroscopic residual tumor (<2cm) or no tumor residual. In the presence of extensive tumor residual, there was no benefi t seen with whole abdomen radiation therapy compared to the other treatment meth ods [10]. Dembo and colleagues analyzed five published trials including the Princess Marga ret Hospital Study in addition to trials performed at Stanford, Salt Lake City, Walter Reed Hospital, and Yale which looked at patients who had surgery followed by whole abdominal radiotherapy [9]. The studies revealed that there were long-

term survivors known to have residual disease after surgery. Approximately 40%-5 0% of these patients who had minimal residual (<2cm) disease were cured [9]. The proportion of survivors was directly related to the amount of residual disease after surgery as well as the presenting stage [9]. These trials were important for two primary reasons. They validated that radiati on therapy is an effective adjuvant therapy in selected patients with ovarian ca ncer. They also revealed that whole abdomen radiation therapy is superior to pel vic radiotherapy alone or with certain chemotherapeutic agents in patients with minimal residual or no residual disease [9]. In general, whole abdominal radiotherapy is well tolerated with low incidence of long term toxicity. Princess Margaret Hospital treated 598 patients between 197 1 and 1985 with whole abdomen radiotherapy. Nausea and vomiting occurred in 61%, diarrhea in 62%, and myelosuppression in 11%. Symptomatic pneumonitis occurred in 4%, and primarily seen with a moving strip technique, which is no longer used currently. The most serious complication seen was small bowel obstruction which was seen in 4% of patients [11]. The risk of small bowel obstruction is related to radiotherapy technique, dose, and fractionations, as well as prior abdominal surgery. With appropriate radiati on therapy techniques and patient selection, the incidence is less than 5% [12]. Salvage with Radiation Therapy There are often high rates of clinical response with cisplatin/paclitaxel based chemotherapy, however, long-term analysis shows high recurrence rates approachin g 40% to 50% [11]. Sedlacek and colleagues found 27 ovarian cancer patients who had recurrent or persistent disease after surgery and chemotherapy. They were ne xt treated with whole abdomen radiotherapy as salvage therapy with curative inte nt. Survival rates from 1 through 5 years was 66%, 48%, 26%, 15%, and 15% respec tively. The study found that patients who had only microscopic residual disease or disease confined to the pelvis had significantly longer recurrence free survi val [13]. At our institution we occasionally use salvage whole abdominal radiotherapy for patients with recurrent or persistent disease after surgery and chemotherapy. On e example is of a 52 year old female diagnosed with ovarian cancer in August 200 0. She underwent exploratory laparotomy with total abdominal hysterectomy and bi lateral salpingo-oopherectomy, omentectomy and cytoreductive surgery. Her surger y was followed by six cycles of Carboplatin and Taxol chemotherapy. In November of 2001, she was found to have a pelvic mass after elevation of her CA-125. She was next treated with several cycles of Carboplatin and Doxil, however she still had persistent pelvic disease. In August of 2002, she underwent surgical resect ion of the mass with no residual gross disease and there was no other evidence o f disease found. Postoperatively she received whole abdomen followed by pelvic a nd tumor bed boost completed November 2002. Currently, she remains without evide nce of disease. Consolidative Radiotherapy Carboplatin/paclitaxel chemotherapy has become the standard treatment after surg ery for patients with epithelial ovarian cancer. Most benefit has been found in patients with intermediate and advanced disease. However, due to the high rate o f recurrence as well as residual gross disease after chemotherapy, consolidative radiotherapy offers the possibility of improving tumor control in selected pati ents [16]. Sorbe and colleagues conducted a trial with 98 patients with stage III ovarian c ancer who had initial cytoreductive surgery followed by chemotherapy with comple te pathologic response. They were next randomly assigned to receive either chemo therapy, whole abdominal radiotherapy, or no further treatment. The patients who had whole abdominal radiotherapy had a significantly better progression-free su

rvival rate (56%) compared to chemotherapy (36%) and no further treatment (33%). At 5 years, the overall survival rates were 69%, 57%, and 65% for radiation, ch emotherapy, and no treatment respectively [14]. Dinniwell and colleagues at Princess Margaret Hospital recently did a prospectiv e study with 29 patients who were diagnosed with epithelial ovarian cancer. They were surgically cytoreduced and given adjuvant carboplatin and paclitaxel chemo therapy. All patients were free of disease by the end of chemotherapy treatment. The 29 patients next received whole abdomen and concurrent pelvic boost irradia tion. After 4 year follow-up, overall survival was 92% and disease-free survival was 57% [16].

Palliative Radiation Therapy Approximately 66% of women with ovarian cancer will develop recurrent disease. T he prognosis after recurrence is very poor. As tumor spreads systemically, women may often present with pain and bleeding. Fox Chase Cancer Center palliatively treated 33 women with ovarian cancer who we re having pain and bleeding. The complete palliative response rate was 51% and o verall (complete and partial) response rate was 79%. Patients were found to have good symptom control for an average of 4 months [12]. Investigators have also found successful relief for pelvic pain, large bowel obs truction, pulmonary compromise, bone pain, and other symptoms of diffuse disease with radiotherapy treatment. Patients with isolated brain metastasis should be treated with surgical resectio n followed by whole brain irradiation and chemotherapy when possible. Patients m ay survive up to 3 years with this combination treatment [15]. Conclusions Surgery followed by whole abdominal radiotherapy has shown favorable results in patients with high risk stage I patients, as well as stage II and stage III pati ents having no residual disease or less than 2cm of residual disease. Currently, chemotherapy is the standard of care after surgery due to the lack of large pro spective randomized trials involving postoperative radiotherapy. Radiation may be utilized as salvage therapy in patients who have failed surgery followed by chemotherapy. Optimal results have been found in patients who have microscopic residual disease or disease confined to the pelvis. Radiotherapy can also be considered as consolidative therapy following optimal c ytoreductive surgery and platinum based chemotherapy for select individuals with intermediate or high risk of relapse. For patients with advanced disease that is unresectable and chemoresistent, radi otherapy has been shown to have an important palliative role in reducing symptom s, such as controlling vaginal or rectal bleeding, pulmonary metastasis, and pai n control.

Nagendra Sai Koneru, M.D.1, Anthony Fyles, M.D.2, William Small Jr., M.D.1 Division of Radiation Oncology; Robert H. Lurie Comprehensive Cancer Center, Nor thwestern University Medical School, Chicago, Illinois1 Division of Radiation Oncology; Princess Margaret Hospital, University of Toront o Toronto, Ontario, Canada2